Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors

Cancer Chemother Pharmacol. 2020 Jul;86(1):97-108. doi: 10.1007/s00280-020-04101-4. Epub 2020 Jun 16.

Abstract

Purpose: To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors.

Methods: In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states.

Results: Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC0-t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0-t was contained within the no-effect limits (0.8-1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported.

Conclusion: A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

Keywords: Adavosertib; Food effect; Oncology; Pharmacokinetics; WEE1.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Biological Availability
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cross-Over Studies
  • Diet, High-Fat / adverse effects*
  • Female
  • Food-Drug Interactions*
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects
  • Pyrazoles / blood
  • Pyrazoles / pharmacokinetics*
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / adverse effects
  • Pyrimidinones / blood
  • Pyrimidinones / pharmacokinetics*

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidinones
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • adavosertib